Prevention of Adverse Effects Caused by CD3 Specific Binding Domains

ABSTRACT

The present invention relates to a glucocorticoid (GC) for use in the amelioration, treatment or prophylaxis of neurological/psychiatric adverse events caused by a CD3 binding domain. Kits comprising a GC, a CD3 binding domain and instructions for use which indicate that the GC is to be employed for the treatment amelioration and/or prophylaxis of neurological adverse events caused by said CD3 binding domain, are also disclosed.

The present invention relates to a glucocorticoid (GC) for use in theamelioration, treatment or prophylaxis of neurological/psychiatricadverse events caused by a CD3 binding domain. Kits comprising a GC, aCD3 binding domain and instructions for use which indicate that the GCis to be employed for the treatment amelioration and/or prophylaxis ofneurological adverse events caused by said CD3 binding domain, are alsodisclosed.

Antibody-based cancer therapies require a target antigen firmly bound tothe surface of cancer cells in order to be active. By binding to thesurface target, the antibody can directly deliver a deadly signal to thecancer cell or indirectly by, for example, recruiting a cytotoxic Tcell, if it is a bispecific antibody. In an ideal treatment scenario, atarget antigen is abundantly present and accessible on every cancer celland is absent, shielded or much less abundant on normal cells. Thissituation provides the basis for a therapeutic window in which a definedamount of the antibody-based therapeutic effectively hits cancer cellsbut spares normal cells.

Though binding domains like antibodies are an effective means intreating many disorders, in particular cancer, their administration isnot necessarily devoid of side effects. Adverse effects may cause areversible or irreversible change in the health status of a patient. Asadverse effects could be harmful and undesired, it is highly desirableto avoid them. However, though it is known that a medicament can causeadverse effects, its prescription and administration could not beavoided or is accepted, since the medicament has an outstandingbeneficial therapeutic effect or may even be life-saving.

In clinical trials, a general distinction can be made between adverseeffects (AEs) and serious adverse effects (SAEs). Specifically, adverseeffects can be classified in 5 grades in accordance with the CommonTerminology Criteria for Adverse Events (CTCAE). Grade 1 relates to mildAE, Grade 2 to moderate AE, Grade 3 to severe AE, Grade 4 tolife-threatening or disabling AE, while Grade 5 means death related toAE.

An adverse effect observed in antibody therapy is the occurrence ofinfusion-related side effects, such as the cytokine release syndrome(“CRS”). Other adverse side effects described to be associated with CRSare fatigue, vomiting, tachycardia, hypertension, back pain, but alsocentral nervous system reactions (CNS reactions, neurological and/orpsychiatric), such as seizures, encephalopathy, cerebral edema, asepticmeningitis, and headache.

Adverse events such as cytokine release and neurological/psychiatricreactions have not only been observed with antibodies binding to the Tcell receptor but also with a CD19×CD3 bispecific single chain antibodybinding to the CD3 part of the T cell receptor (called Blinatumomab(MT103)). Blinatumomab (MT103) is a lymphoma-directed, recombinantbispecific single-chain CD19×CD3 antibody that binds to CD19 on thesurface of almost all B cells and B tumor cells and concomitantly canengage a T cell, thereby triggering the T-cell to kill the target B cellor B tumor cell. Blinatumomab consists of four immunoglobulin variabledomains assembled into a single polypeptide chain. Two of the variabledomains form the binding site for CD19, a cell surface antigen expressedon most B cells and B tumor cells. The other two variable domains formthe binding site for the CD3 complex on T cells. Blinatumomab isdesigned to direct the body's cytotoxic, or cell-destroying, T cellsagainst tumor cells, and represent a new therapeutic approach to cancertherapy. Blinatumomab is presently in clinical trials.

As described, for instance, in WO 99/54440, adverse effects have beenobserved in a previous study performed with Blinatumomab applied inrepeated bolus infusions to a patient with B-cell derived chroniclymphatic leukaemia (B-CLL). As shown in FIGS. 19 and 20 of WO 99/54440,release of TNF, IL-6 and IL-8 has been found in response to each of theadministered 20 minute-infusions of 3 microgram and 10 microgram of thementioned bispecific single chain antibody, respectively, with cytokinerelease after each administration. Maximal cytokine release was observedafter administration of 10 microgram of bispecific single chainantibody. In a following clinical trial study, in which escalating dosesof the CD19×CD3 bispecific single chain antibody have been administeredto patients with B cell malignancies as bolus infusions, adverse effectshave also been observed. According to a retrospective analysis, 7 out of22 patients showed an early neurological reaction, including, forexample, confusion, ataxia, speech disorder, or disorientation.

As shown in Bargou et al. (Science 321 (2008): 974-7), doses as low as0.005 milligrams per square meter per day continuously administered tonon-Hodgkin's lymphoma patients over four weeks led to an elimination oflymphoma target cells in blood. Partial and complete tumor regressionswere first observed at a dose level of 0.015 milligrams/m²/d, and allseven patients treated at a dose level of 0.06 milligrams/m²/dexperienced a tumor regression (Bargou et al., cited above). TheCD19×CD3 bispecific single chain antibody also led to clearance of tumorcells from bone marrow and liver. However, though this (still ongoing)study established clinical proof of concept for the therapeutic potencyof the CD19×CD3 bispecific single chain antibody format in the treatmentof blood-cell derived cancer, neurological reactions have been found inthe course of the aforementioned clinical trial. In order to get theseundesired side effects under control, the mode of administration of theCD19×CD3 bispecific single chain antibody has been changed in that ithas been switched over from bolus infusion to a continuous intravenousadministration of said antibody for a longer period of time.Accordingly, since Blinatumomab is a very promising candidate medicamentfor treating non-Hodgkin's lymphoma (NHL), such as, diffuse large B-celllymphoma (DLBCL), follicular lymphoma and mantle cell lymphoma (MCL),acute lymphoblastic leukemia (ALL), and/or chronic lymphocytic leukemia(CLL), it is highly desirable to reduce or even completely avoidundesired side-effects in the treatment of patients in need thereof withthe CD19×CD3 bispecific single chain antibody.

It is however difficult to design a CD19×CD3 antibody-based therapy,which does not cause CNS (neurological and/or psychiatric) reactions or,to put it differently, it is desired to provide a CD19×CD13antibody-based medical therapies with increased patient tolerability,i.e., reduced or even no undesired adverse effects such as CNSreactions.

Though pharmaceutical means and methods which allow a more gradualactivation of T cell populations (see WO 2007/068354) already helped toavoid significant adverse side effects in patients treated with theCD19×CD3 bispecific single chain antibody, neurological reactions couldunfortunately not be prevented by these measures, in particular in casesin which doses of more than 5 to 10 microgram per square meter per day(i.e. 24 h) of the antibody have been administered.

Thus, the technical problem underlying the present invention was toprovide means and methods to overcome the above problems.

The present invention addresses this need and thus provides embodimentsconcerning means and methods for use in the amelioration, treatment orprophylaxis of neurological adverse effects caused by a CD3 bindingdomain, such as a CD19×CD3 bispecific antibody.

These embodiments are characterized and described herein and reflectedin the claims.

It must be noted that as used herein, the singular forms “a”, “an”, and“the”, include plural references unless the context clearly indicatesotherwise. Thus, for example, reference to “a reagent” includes one ormore of such different reagents and reference to “the method” includesreference to equivalent steps and methods known to those of ordinaryskill in the art that could be modified or substituted for the methodsdescribed herein.

All publications and patents cited in this disclosure are incorporatedby reference in their entirety. To the extent the material incorporatedby reference contradicts or is inconsistent with this specification, thespecification will supersede any such material. Unless otherwiseindicated, the term “at least” preceding a series of elements is to beunderstood to refer to every element in the series. Those skilled in theart will recognize, or be able to ascertain using no more than routineexperimentation, many equivalents to the specific embodiments of theinvention described herein. Such equivalents are intended to beencompassed by the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integer or step.

In each instance herein any of the terms “comprising”, “consistingessentially of” and “consisting of” may be replaced with either of theother two terms.

Several documents are cited throughout the text of this specification.Each of the documents cited herein (including all patents, patentapplications, scientific publications, manufacturer's specifications,instructions, etc.), whether supra or infra, are hereby incorporated byreference in their entirety. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

In view of the adverse events described in the sections above,particularly the adverse CNS effects including neurological reactionsobserved with CD3 specific binding domains, the finding that theseadverse effects can be mitigated or even prevented if the administrationof the CD3-specific binding domain is accompanied or preceded by theadministration of a glucocorticoid, is definitely remarkable.

Specifically, the present inventors observed that those patients, towhom a CD19×CD3 bispecific antibody was administered, encounteredneurological side effects, and, further, that these neurological sideeffects could be prevented or alleviated by means of a glucocorticoid(pre) and/or (co)therapy.

Accordingly, the present invention establishes for the first time thatglucocorticoids such as dexamethasone mitigate or even preventneurological/psychiatric adverse effects which might occur in the courseof a treatment with CD3 specific binding domains (see also the Examplesection).

Glucocorticoids (GCs) are still the most widely used immunosuppressiveagents for the treatment of inflammatory disorders and autoimmunediseases. Glucocorticoids (GC) are a class of steroid hormones that bindto the glucocorticoid receptor (GR), which is present in almost everyvertebrate animal cell, including humans. These compounds are potentanti-inflammatory agents, regardless of the inflammation's cause.Glucocorticoids suppress, inter alia, the cell-mediated immunity byinhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4,IL-5, IL-6, IL-8 and IFN-γ.

Cortisone which belongs to the group of GCs is an important therapeuticdrug which is used to fight many ailments ranging from Addison's diseaseto rheumatoid arthritis. Ever since the discovery of its anti-rheumaticproperties, which led to its acclaim as a wonder drug, many derivativesof cortisone with enhanced properties to better fight a specific ailmenthave been produced. Cortisone belongs to a group of steroids known ascorticosteroids. These steroids are produced by the adrenal cortex,which is the outer part of the adrenal glands, near the kidneys. Thecorticosteroids are divided into two main groups: the glucocorticoids(GCs), which control fat, protein, calcium and carbohydrate metabolism,and the mineralocorticoids controlling sodium and potassium levels.Cortisone belongs to the former group, i.e. to the GCs. Cortisone andits many derivatives are used for a variety of diseases. Cortisone alsohelped to make organ transplants a reality due to its ability tominimize the defence reaction of the body towards foreign proteinspresent in the implanted organ and thus damage the functionality of theimplanted organ. However, despite clinical use during more than 50years, the specific anti-inflammatory effects of GC on differentcellular compartments of the immune system are not yet clear. GCs affectnearly every cell of the immune system, and there is growing evidencefor cell type-specific mechanisms.

In a first embodiment, the present invention relates to a glucocorticoid(GC) for use in the amelioration, treatment or prophylaxis ofneurological adverse effects caused by a CD3 binding domain. As outlinedabove, these unwanted adverse effects frequently accompany a therapywith a CD3 binding domain. The present invention remedies thesedisadvantages and provides glucocorticoid(s) for use in theamelioration, treatment or prophylaxis of neurological adverse effectsin a patient wherein said patient is subject to therapy with a CD3binding domain. Accordingly, the present invention relates to aglucocorticoid (GC) for use in a method in the amelioration, treatmentor prophylaxis of neurological adverse effects caused by a CD3 bindingdomain.

The present invention thus relates to a GC for use in the amelioration,treatment or prophylaxis of neurological adverse effects caused by a CD3binding domain in a human patient, wherein said GC is to be administeredprior to, concurrently with and/or subsequently to the administration ofsaid binding domain.

Also, the present invention relates to a method of amelioration,treatment or prophylaxis of neurological adverse effects caused by a CD3binding domain, said method comprising administering to a patient inneed thereof a glucocorticoid (GC). The GC is preferably administered inan amount which is sufficient to ameliorate, treat or prevent saidneurological adverse effects caused by a CD3 binding domain.

The neurological side effects are “caused by” the administration of aCD3 binding domain to a patient. The term “caused by” means that the CD3binding domain is causative for the neurological side effects. Theskilled person can easily evaluate whether the administration a CD3binding domain is causative for a neurological effect or not. To thisend, it is just required to closely monitor the patient during thecourse of the administration and to detect, thereby, that theadministration of the CD3 binding domain was causative for theneurological side effects. Likewise, it is envisaged to discontinue theadministration of the CD3 binding domain and to evaluate whether theneurological side effects are thereby ameliorated or even fade away,which also indicates that the neurological side effects were caused bysaid CD3 binding domain.

The term “glucocorticoid” means compounds that bind, preferablyspecifically, to the glucocorticoid receptor. Said term includescompound(s) selected from the group consisting of cortisone, cortisol(hydrocortisone), cloprednol, prednisone, prednisolone,methylprednisolone, deflazacort, fluocortolone, triamcinolone,(including triamcinolonacetonide), dexamethasone, betamethasone,cortivazol, paramethasone, flusticasonepropionate,triamcinolonacetonide. and/or fluticasone (includingflusticasonepropionate), including pharmaceutically acceptablederivatives thereof. In the context of the embodiments of the presentinvention, the mentioned compounds may be used alone or in combination.Dexamethasone is preferred. The present invention is however not limitedto the above mentioned specific GCs. It is envisaged that all substanceswhich already are or will be classified as a “glucocorticoid”, may beemployed in the context of the present invention as well. Such futureglucocorticoids include compounds which specifically bind to andactivate the glucocorticoid receptor. The term “specifically binds tothe GC receptor” means in accordance with the present invention that theGC (or a compound which is assumed to act like a GC) associates with(e.g., interacts with) the GC receptor (also known as NR3C1) to astatistically significant degree as compared to association withproteins/receptors generally (i.e., non-specific binding). When the GCreceptor binds to glucocorticoids, its primary mechanism of action isthe regulation of gene transcription. In the absence of GC, theglucocorticoid receptor (GR) resides in the cytosol complexed with avariety of proteins including Heat shock protein 90 (hsp90), the heatshock protein 70 (hsp70) and the protein FKBP52 (FK506-binding protein52). The binding of the GC to the glucocorticoid receptor (GR) resultsin release of the heat shock proteins. It is thus envisaged that afuture GC, or a pharmaceutically acceptable derivative or salt of a GCis preferably able to bind to the GC receptor and to release the abovementioned heat shock proteins. The activated GR complex up-regulates theexpression of anti-inflammatory proteins in the nucleus or represses theexpression of pro-inflammatory proteins in the cytosol (by preventingthe translocation of other transcription factors from the cytosol intothe nucleus).

In a preferred embodiment, said GC is selected from the most clinicalused and relevant GCs like dexamethasone, fluticasonepropionate,prednisolone, methylprednisolone, betamethasone, triamcinolonacetonideor combinations thereof.

In an even more preferred embodiment, said GC is dexamethasone.

Dexamethasone has the highest glucocorticoid potency of the mostcommonly used steroids and also has the longest half-life (see Tablebelow). But a person skilled in the field can select one of the otherknown glucocorticoids, some of which are disclosed herein, and select anappropriate effective dose to ameliorate or prevent neurological adverseevents that may result from the treatment of a patient in need thereof,such as a DLBCL patient with a bispecific antibody molecule thatcontains a CD3 binding domain, such as CD19×CD3 bispecific single chainantibody.

Relative Approx. Relative anti- mineralo- equiv. inflammatory corticoidBiologic dose (glucocorticoid) Na⁺ retain- half-life Agent (mg) potencying) potency (hrs) Cortisone 25 0.8 0.8  8-12 Hydrocortisone 20 1 1 8-12 Prednisone 5 4 0.8 18-36 Prednisolone 5 4 0.8 18-36 Methylpred- 55 0.5 18-36 nisolone Dexamethasone 0.75 25 0 36-54

Dexamethasone also possesses a beneficial effect in malignant centralnervous system (CNS) disease (e.g. CNS lymphoma or brainmetastases)—possibly due to specific penetration to the CNS. It is alsopreferentially (over other steroids) used to treat brain edema. Althoughcorticosteroids decrease capillary permeability in the tumor itself, ithas been found in animal models that dexamethasone may act differentlyand decrease edema by effects on bulk flow away from the tumor (Molnar,Lapin, & Goothuis, 1995, Neurooncol. 1995; 25(1):19-28.

For the clinical trials in connection with the application of a CD19×CD3bispecific single chain antibody for the treatment of tumorous mass oflymph node tissue and/or extranodal lymphoma caused by DLBCL, thepresent inventors had to develop a treatment regime which was efficientand would be well tolerated by most of the patients. To this end, thepresent inventors applied a step-wise application of a CD19×CD3bispecific single chain antibody in that 5/15/60 μg/m²/24 h wasadministered to patients. Thereby, adverse effects, in particularneurological/psychiatric events could be reduced in number, amelioratedand even prevented. Also contemplated in the step-wise administration ofa CD19×CD3 bispecific single chain antibody is a treatment regime usingtwo of the dosages, such as 5/15 μg/m²/24 h, 5/60 μg/m²/24 h, or 15/60μg/m²/24 h for the duration of the patient's treatment. The appropriatedosage can be selected by the clinician on the basis of efficacy,tolerability and safety with a minimum of adverse effects in thepatient.

But the inventors also contemplate the treatment of tumorous mass oflymph node tissue and/or extranodal lymphoma caused by DLBCL to includethe continuous administration of a flat dose without escalation to asubsequent higher dose. For example, the present treatment regimeincludes the administration of 5 μg/m²/24 h, 15 μg/m²/24 h, or 60μg/m²/24 h of a CD19×CD3 bispecific single chain antibody until theconclusion of a course of the treatment up to 8 weeks [56 days] withgood tolerability and no adverse effects, and even longer if determinedto be safe and effective.

It is generally preferred that each of the doses disclosed herein can beconverted from amount (in μg)/m²/d into μg/d by multiplying therespective dose with the factor 1.9. Accordingly, each of the dosesdisclosed herein can be applied in the methods and uses by multiplyingit with the factor 1.9. For example, a dose of 5 μg/m²/d is convertedinto 9.5 μg/d, a dose of 15 μg/m² is converted into 28.5 μg/m²/and adose of 60 μg/m²/is converted into 114 μg/m². It is preferred that adecimal digit that results from the multiplication is either rounded upor rounded down, respectively, to a whole number. For example, a dose of9.5 μg/d can be rounded down to 9 μg/d and a dose of 28.5 μg/m² can berounded down to 28 μg/d. Likewise, a dose of 9.5 μg/d can be rounded upto 10 μg/d and a dose of 28.5 μg/m² can be rounded up to 29 μg/d.

The term “pharmaceutically acceptable derivatives” includes salts,esters, enol ethers, enol esters, acetals, ketals, orthoesters,hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugsthereof. Such derivatives may be readily prepared by those of skill inthis art using known methods for such derivatisation.

The dose of the GC that is to be used in accordance with the embodimentsof the present invention is not limited, i.e. it will depend on thecircumstances of the individual patient. GC can be administeredintravenously or orally. Preferred dosages of the GC include, however,between 1 to 6 mg (dexamethasone equivalent) at the lower end of dosingto 40 mg/d (dexamethasone equivalent). Said dosage can be administeredall at once or subdivided into smaller dosages (see the appendedexamples). Particularly preferred is a dosage of 4 to 24 mg/d. Dailydosages of 4, 8, 12, 16, 20 or 24 mg/d are even more preferred. A dosageof 1×4 mg per day, 2×4 mg per day, 1×8 mg per day; 1×4 mg plus 1×8 mgper day, 2×8 mg per day, 2×10 mg per day or 5×4 mg per day and 3×8 mgper day of dexamethasone is particularly preferred. “d” denotes one day.Further dosage regimens are derivable from the appended examples. Alldosages given in this paragraph refer to dexamethasone equivalents.

An “adverse effect”, which is sometimes also denoted as “side effect” or“adverse event (in clinical studies)” is a harmful and undesired effectresulting from medication in the treatment of a patient with a CD3binding domain. A “neurological/psychiatric adverse effect” which issometimes also denoted as neurological symptom or CNS adverse effect,includes conditions of a human patient such as all forms of pain,including headache and back pain, muscle weakness or incoordination,abnormal sensations in the skin, and disturbances of the senses,seizures, encephalopathy, cerebral edema, confusion, ataxia, speechdisorder, hallucinations, apraxia, paresis, tremor, headache, ordisorientation. A neurological effect as used herein preferably includespsychiatric adverse effects. Sometimes, however, the terms “neurologicaladverse effect” and “psychiatric adverse effects” can be usedinterchangeable.

Specifically, neurological/psychiatric reactions observed duringtreatment with a CD3 binding domain include for example confusion anddisorientation. “Confusion” as used herein refers to loss of orientationwhich is the ability to place oneself correctly in the world by time,location, and personal identity, and often memory which is the abilityto correctly recall previous events or learn new material. The patientsusually have difficulties to concentrate and thinking is not onlyblurred and unclear but often significantly slowed down. Patients withneurological/psychiatric reactions also suffer from loss of memory.Frequently, the confusion leads to the loss of ability to recognizepeople and/or places, or to tell time and the date. Feelings ofdisorientation are common in confusion, and the decision-making abilityis impaired. Neurological reactions further comprise blurred speechand/or word finding difficulties. This disorder may impair both, theexpression and understanding of language as well as reading and writing.Besides urinary incontinence, also vertigo and dizziness may accompanyneurological reactions in some patients.

The herein mentioned “patient” is a mammal, preferably a human, who willbe or (already) is treated with a CD3 binding domain.

It is also envisaged that the patient is characterized by a B/T-cellratio of less than 1:5 (see PCT/EP2010/066207).

In a preferred embodiment, the patient is suspected/assumed to compriseor already comprises malignant CD19 positive lymphocytes (in particularB cells). In the latter case, said patient has already been diagnosed tocomprise such cells. These malignant CD19 positive lymphocytes (inparticular B cells) are present in a patient developing and/or sufferingfrom leukemia and/or lymphoma.

A “CD3 binding domain” characterizes in connection with the presentinvention a binding domain which comprises a framework region and an“antigen-binding-site” or “antigen-interaction site” which is able tospecifically interact with a CD3 antigen. Said binding/interaction isalso understood to define a “specific recognition”. The term“specifically interact/interacting” means in accordance with thisinvention that the binding domain is capable of binding to at least two,preferably at least three, more preferably at least four amino acids ofthe CD3 antigen, preferably the CD3 epsilon antigen, and more preferablythe human CD3 epsilon antigen. Such CD3 binding domains as well asspecific CD3 epsilon epitopes are well-known to the skilled person andexemplified in great detail for example in WO2008119567 or inWO2008119566, both of which are included herein by way of referencethereto.

As used herein, “CD3” denotes a molecule expressed as part of the T cellreceptor and has the meaning as typically ascribed to it in the priorart. In human, it encompasses in individual or independently combinedform all known CD3 subunits, for example CD3 epsilon, CD3 delta, CD3gamma, CD3 zeta, CD3 alpha and CD3 beta. The human CD3 epsilon isindicated in GenBank Accession No.NM_(—)000733.

A CD3 binding molecule which binds to the human CD3 epsilon ispreferred. The CD3 epsilon epitope disclosed in great detail inWO2008119567 or in WO2008119566 is even more preferred.

The term “framework” includes a scaffold for antigen-binding sites. Forexample, such a scaffold could be provided by protein A, in particular,the Z-domain thereof (affibodies), ImmE7 (immunity proteins), BPTI/APPI(Kunitz domains), Ras-binding protein AF-6 (PDZ-domains), charybdotoxin(Scorpion toxin), CTLA-4, Min-23 (knottins), lipocalins (anticalins),neokarzinostatin, a fibronectin domain, an ankyrin consensus repeatdomain or thioredoxin (Skerra, Curr. Opin. Biotechnol. 18, 295-304(2005); Hosse et al., Protein Sci. 15, 14-27 (2006); Nicaise et al.,Protein Sci. 13, 1882-1891 (2004); Nygren and Uhlen, Curr. Opin. Struc.Biol. 7, 463-469 (1997)).

A preferred “framework” is, in the context of the present invention, theart-recognized portions of an antibody variable region that existbetween the more divergent (i.e., hypervariable) complementaritydetermining regions (CDRs) within the variable region of an antibody.Such framework regions are typically referred to as frameworks 1 through4 (FR1, FR2, FR3, and FR4) and provide a scaffold for the presentationof the six CDRs (three from the heavy chain and three from the lightchain) in three dimensional space, to form an antigen-binding surface.

A preferred example of a CD3 binding domain in line with the presentinvention is an antibody. The binding domain may be a monoclonal orpolyclonal antibody or derived from a monoclonal or polyclonal antibody.The term “antibody” comprises derivatives or functional fragmentsthereof which still retain the binding specificity. Techniques for theproduction of antibodies are well known in the art and described, e.g.in Harlow and Lane “Antibodies, A Laboratory Manual”, Cold Spring HarborLaboratory Press, 1988 and Harlow and Lane “Using Antibodies: ALaboratory Manual” Cold Spring Harbor Laboratory Press, 1999. The term“antibody” also comprises immunoglobulins (Ig's) of different classes(i.e. IgA, IgG, IgM, IgD and IgE) and subclasses (such as IgG1, IgG2etc.).

The definition of the term “antibody” also includes embodiments such aschimeric, single chain, de-immunized and humanized antibodies, as wellas antibody fragments, like, inter alia, Fab fragments. Antibodyfragments or derivatives further comprise F(ab′)2, Fv, scFv fragments orsingle domain antibodies, single variable domain antibodies orimmunoglobulin single variable domain comprising merely one variabledomain, which might be VH or VL, that specifically bind to an antigen orepitope independently of other V regions or domains; see, for example,Harlow and Lane (1988) and (1999), cited above. Such immunoglobulinsingle variable domain encompasses not only an isolated antibody singlevariable domain polypeptide, but also larger polypeptides that compriseone or more monomers of an antibody single variable domain polypeptidesequence.

Bispecific antibody formats are preferred; however other multispecificantibody formats (trispecifc, tetrabodies etc.) are not excluded.

In a further preferred embodiment, the present invention relates tomethods of treatment/dosage regimen which employ CD19×CD3 bispecificantibodies, comprising a first binding domain capable of binding to anepitope of human CD3 epsilon chain and a second binding domain capableof binding to human CD19. Examples for bispecific molecules according tothe methods of the invention are described in great detail in WO99/54440 and WO 2004/106381 and WO 2008/119565. All the specificCD19×CD3 bispecific antibodies disclosed therein, including theirvariants, fragments, equivalents etc. are particularly preferredCD19×CD3 bispecific antibodies of the present invention.

As used herein, a “CD19×CD3 bispecific antibody” (including a CD19×CD3bispecific single chain antibody) denotes a single polypeptide chaincomprising two binding domains. Such single chain antibodies arepreferred in the context of the methods/dosage regimen of the presentinvention. Each binding domain comprises at least one variable regionfrom an antibody heavy chain (“VH or H region”), wherein the VH regionof the first binding domain specifically binds to the CD3 epsilonmolecule, and the VH region of the second binding domain specificallybinds to CD19. The two binding domains are optionally linked to oneanother by a short polypeptide spacer. A non-limiting example for apolypeptide spacer is Gly-Gly-Gly-Gly-Ser (G-G-G-G-S) and repeatsthereof. Each binding domain may additionally comprise one variableregion from an antibody light chain (“VL or L region”), the VH regionand VL region within each of the first and second binding domains beinglinked to one another via a polypeptide linker, for example of the typedisclosed and claimed in EP 623679 B1, but in any case long enough toallow the VH region and VL region of the first binding domain and the VHregion and VL region of the second binding domain to pair with oneanother such that, together, they are able to specifically bind to therespective first and second binding domains. Such CD19CD3 bispecificsingle chain antibodies are described in great detail in WO 99/54440 andWO 2004/106381.

The human CD19 protein is indicated in GenBank Accession No. AAA69966.

Preferably, the bispecific antibody applied in the methods/dosageregimens of the present invention has the domain arrangementVL(CD19)-VH(CD19)-VH(CD3)-VL(CD3).

It is, however, also envisaged that the methods of the invention can becarried out with CD19×CD3 bispecific single chain antibodies of otherdomain arrangements, such as

VH(CD19)-VL(CD19)-VH(CD3)-VL(CD3), VL(CD19)-VH(CD19)-VL(CD3)-VH(CD3),VH(CD19)-VL(CD19)-VL(CD3)-VH(CD3), VL(CD3)-VH(CD3)-VH(CD19)-VL(CD19),VH(CD3)-VL(CD3)-VH(CD19)-VL(CD19), VL(CD3)-VH(CD3)-VL(CD19)-VH(CD19), orVH(CD3)-VL(CD3)-VL(CD19)-VH(CD19).

A preferred CD19×CD3 bispecific antibody applied in the methods of thepresent invention comprises the

-   (a) anti-CD3 CDRs of the heavy chain shown as CD3 CDR-H1 in SEQ ID    NO: 11 (RYTMH), more preferably in SEQ ID NO: 11 (GYTFTRYTMH), CD3    CDR-H2 in SEQ ID NO: 12 (YINPSRGYTNYNQKFKD) and CD3 CDR-H3 in SEQ ID    NO: 13 (YYDDHYCLDY); and/or-   (b) anti-CD3 CDRs of the light chain shown as CD3 CDR-L1 in SEQ ID    NO: 14 (RASSSVSYMN), CD3 CDR-L2 in SEQ ID NO: 15 (DTSKVAS) and CD3    CDR-L3 in SEQ ID NO: 16 (QQWSSNPLT); and/or-   (c) anti-CD19 CDRs of the heavy chain shown as CD19 CDR-H1 in SEQ ID    NO: 17 (SYWMN), more preferably in SEQ ID NO: 17 (GYAFSSYWMN), CD19    CDR-H2 in SEQ ID NO: 18 (QIWPGDGDTNYNGKFKG) and CD19 CDR-H3 in SEQ    ID NO: 19 (RETTTVGRYYYAMDY); and/or-   (d) anti-CD19 CDRs of the light chain shown as CD19 CDR-L1 in SEQ ID    NO: 20 (KASQSVDYDGDSYLN), CD19 CDR-L2 in SEQ ID NO: 21 (DASNLVS) and    CD19 CDR-L3 in SEQ ID NO: 22 (QQSTEDPWT).

It is more preferred that the CD19×CD3 bispecific antibody applied inthe methods of the present invention comprises the CD3 CDRs of the heavyand light chain. Even more preferably, the CD19×CD3 bispecific antibodyapplied in the methods of the present invention comprises the CD3 CDRsof the heavy and light chain as well as the CD19 CDRs of the heavy andlight chain.

The CDRs referred to herein are in accordance with the Kabat numberingsystem. The Kabat numbering scheme is a widely adopted standard fornumbering the residues in an antibody in a consistent manner (Kabat etal., Sequences of Proteins of Immunological Interest, 1991).

Alternatively, it is preferred that the CD19×CD3 bispecific antibodyapplied in the methods of the present invention comprises the

-   (a) CD19 variable heavy chain shown in SEQ ID NO: 3 (nucleotide    sequence is shown in SEQ ID NO: 4); and/or-   (b) CD19 variable light chain shown in SEQ ID NO: 5 (nucleotide    sequence is shown in SEQ ID NO: 6); and/or-   (c) CD3 variable heavy chain shown in SEQ ID NO: 7 (nucleotide    sequence is shown in SEQ ID NO: 8); and/or-   (d) CD3 variable light chain shown in SEQ ID NO: 9 (nucleotide    sequence is shown in SEQ ID NO: 10).    More preferably, the CD19×CD3 bispecific antibody applied in the    methods of the present invention comprises the CD19 variable heavy    and light chain and/or the CD3 variable heavy and light chain. Even    more preferably, the CD19×CD3 bispecific antibody applied in the    methods of the present invention comprises the CD19 variable heavy    and light chain as well as the CD3 variable heavy and light chain.

In another alternative, it is also preferred that said bispecific singlechain antibody comprises an amino acid sequence selected from the groupconsisting of

-   (a) an amino acid sequence as depicted in SEQ ID NO: 1;-   (b) an amino acid sequence encoded by a nucleic acid sequence as    shown in SEQ ID NO: 2;-   (c) an amino acid sequence encoded by a nucleic acid sequence having    at least 70%, 80%, 90%, 95% or 99% identity to a nucleic acid    sequence of (b), wherein said amino acid sequence is capable of    specifically binding to CD3 and CD19; and-   (d) an amino acid sequence encoded by a nucleic acid sequence which    is degenerate as a result of the genetic code to a nucleotide    sequence of (b), wherein said amino acid sequence is capable of    specifically binding to CD3 and CD19.

It is to be understood that the sequence identity is determined over theentire amino acid sequence. For sequence alignments, for example, theprograms Gap or BestFit can be used (Needleman and Wunsch J. Mol. Biol.48 (1970), 443-453; Smith and Waterman, Adv. Appl. Math 2 (1981),482-489), which is contained in the GCG software package (GeneticsComputer Group, 575 Science Drive, Madison, Wis., USA 53711 (1991). Itis a routine method for those skilled in the art to determine andidentify an amino acid sequence having e.g. 70%, 80%, 90%, 95%, 96%,97%, 98% or 99% sequence identity to the amino acid sequences of theCD19×CD3 bispecific antibody described herein (preferably MT103). Forexample, according to Crick's Wobble hypothesis, the 5′ base on theanti-codon is not as spatially confined as the other two bases, andcould thus have non-standard base pairing. Put in other words: the thirdposition in a codon triplet may vary so that two triplets which differin this third position may encode the same amino acid residue. Saidhypothesis is well known to the person skilled in the art (see e.g.http://en.wikipedia.org/wiki/Wobble_Hypothesis; Crick, J Mol Biol 19(1966): 548-55). It is furthermore a routine procedure for those skilledin the art to determine cytotoxic activity of such an amino acidsequence having e.g. 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% A sequenceidentity to the nucleotide or amino acid sequences of the CD19×CD3bispecific single chain antibody described herein. Cytotoxic activity ofthe CD19×CD3 bispecific single chain antibody or an antibody constructhaving e.g. 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% A sequence identityto the amino acid sequences of the CD19×CD3 bispecific single chainantibody can be determined by methods as illustrated e.g. in WO99/54440.

Particularly preferred, said CD19×CD3 bispecific single chain antibodyhas the amino acid sequence shown in SEQ ID NO: 1.

Also particularly preferred is the CD19×CD3 bispecific antibody MT103described in WO 99/54440 as well as those CD19×CD3 bispecific antibodiesdescribed in WO 2004/106381 and WO 2008/119565.

The present invention also relates to a CD19×CD3 bispecific antibody foruse in the treatment of malignant CD19 positive lymphocytes in a humanpatient, wherein said antibody is to be administered prior to,concurrently with or subsequently to the administration of a GC.

The present invention further relates to a method for

-   (i) administering a CD3 binding domain, such as a CD19×CD3    bispecific antibody to a human patient, or-   (ii) treating malignant CD19 positive lymphocytes in a human patient    by administering the CD3 binding domain;    wherein said antibody is to be administered prior to, subsequently    to and/or in combination with a GC.

The administration of the CD3 binding domain or of a pharmaceuticalcomposition comprising said CD3 binding domain is preferably anintravenous administration. The administration of the GC or apharmaceutical composition comprising said GC is preferably intravenousor per os (p.o.). They may be administered as a bolus injection orcontinually (continuously), with continually being preferred. Acontinual administration refers to an administration which isessentially without interruption. “Essentially without interruption”includes a continual administration usually without an uninterruptedflow or spatial extension. By way of example, WO 2007/068354 discloses atreatment regimen which is specifically included herein by way ofreference thereto. Other treatment regimens which are envisaged in thecontext of the present invention are disclosed in PCT/EP2010/066207.

In a preferred embodiment, a first dose of the CD3 binding domain isadministered for a first period of time; and optionally consecutively asecond dose of the CD3 binding domain is administered for a secondperiod of time, wherein the second dose exceeds the first dose.

The term “exceeds” means that the second period of time is at least oneday longer than the first period of time.

In another preferred embodiment of the present application, a third doseof the CD3 binding domain is administered for a third period of timeafter administering a first and second dose for a first and secondperiod of time. Accordingly, the present invention provides athree-stage (three-step) administration scheme (dosage regimen) to beapplied in the uses and methods described herein.

In a further preferred embodiment, the present invention encompasses thecontinuous administration of a flat dose of the CD3 binding domainwithout escalation to a subsequent higher dose. For example, the presentadministration includes the administration of 60 μg/m²/24 h, 15 μg/m²/24h or 5 μg/m²/24 h of a CD3 binding domain, in particular a CD19×CD3bispecific single chain antibody until the conclusion of a course of thetreatment up to 8 weeks [56 days] and even longer if determined to besafe and effective.

More specifically, in a three-stage administration scheme, dexamethasoneis administered in the range of between 6 and 48 hours before theadministration of the first dose of the CD3 binding domain, morepreferably between 6 and 12 hours, and more preferably 12 hours, beforethe first dose administration. Then approximately 1 hour before (range15 min-2 h including 30 min, 45 min, 60 min, 75 min, 90 min) the firstdose of the binding domain is administered, a dose of dexamethasone isagain administered to the patient. Then dexamethasone is administered 1or more days, preferably 2 to 3 days, after the first dose of theantibody, preferably on the two days after the first binding domainadministration and administered 1 or more days, preferably 2 or moredays after each dose increase, preferably on the two days after theadministration of the dose increase of the binding domain. Each of thedexamethasone doses is preferably between 6 and 40 mg, and preferably atapproximately 20 or 24 mg per dose.

The time range between 6 and 48 hours includes the administration of thedexamethasone dose and means that the times prior to the firstadministration of the binding domain are 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 and 48 hours.Similarly, the preferred time range between 6 and 12 hours includes theadministration of the dexamethasone dose prior to the firstadministration of the binding domain and includes 6, 7, 8, 9, 10, 11 and12 hours,

In a further embodiment, dexamethasone is administered for a period oftwo, three, four or five days during which the dose of the bindingdomain is increased. For example, dexamethasone is administered at afirst point of time in a dose of 6 to 40 mg or 6 to 48 mg, preferably20, 24, 28, 32, 36, 40, 44 or 48 mg, with 20 or 24 mg being preferred,at a second point of time in a dose of preferably 8, 12, 16, 20, or 24mg, with 16 mg being preferred and/or at a third point of time in a doseof preferably 2, 4, 6, 8, 10 or 12 mg, with 8 mg being preferred. It mayalso be administered at a fourth point of time or fourth and fifth pointof time in a dose of preferably 2, 4, 6, 8, 10 or 12 mg, with 8 mg beingpreferred.

It is also envisaged that the human patient of the present invention ischaracterized by a B/T-cell ratio of less than 1:5 (seePCT/EP2010/066207). As disclosed in great detail in PCT/EP2010/066207,neurological side effects frequently accompany the administration of aCD19×CD3 bispecific antibody in patients which are characterized by aB/T-cell ratio of less than 1:5. The prevention, amelioration ortreatment of neurological side effects caused by a CD3 binding domain byway of a GC therapy disclosed herein, is however also applicable topatients which are characterized by a B/T-cell ratio of more than 1:5(see PCT/EP2010/066207).

The present invention also relates to a (pharmaceutical) kit or packagecomprising a GC and/or a CD3 binding domain, and instructions and/or animprint indicating that the GC is to be employed for the treatmentamelioration and/or prophylaxis of neurological adverse events caused bysaid CD3 binding domain. Said GC and CD3 binding domain are preferablypackaged together in one sealed package or kit. It is also envisagedthat the package or kit of the present invention, further comprisesmeans to administer the GC and/or Cd3 binding domain to a patient and/orbuffers, vials, teflon bags or infusion bags which are normally used forthe infusion of therapeutic agents. “Means” thereby includes one or morearticle(s) selected from the group consisting of a syringe, a hypodermicneedle, a cannula, a catheter, an infusion bag for intravenousadministration, intravenous vehicles, vials, buffers, stabilizers,written instructions which aid the skilled person in the preparation ofthe respective doses and infusions of the invention etc.

By “complete response” is intended an absence of clinically detectabledisease with normalization of any previously abnormal imaging studiessuch as radiographic studies. Such a response preferably persists for atleast 4 to 8 weeks, sometimes 6 to 8 weeks or more than 8, 10, 12, 14,16, 18 or 20 weeks or longer, following treatment according to theinvention. Alternatively, an improvement in the disease may becategorized as being a partial response.

Preferably, complete remission in ALL is defined as a blast count below5% in the bone marrow and recovery of bone marrow function. Detailedremission and response definitions for NHL patients are used accordingto Cheson et al., 1999, J Clin Oncol. April; 17(4):1244

By “partial response” is intended at least about a 50% decrease in allmeasurable tumor burden (i.e., the number of malignant cells present inthe patient, or the measured bulk of tumor masses) in the absence of newlesions and persisting for 4 to 8 weeks or more than 8, 10, 12, 14, 16,18 or 20 weeks or longer. A “complete response” does, however, notnecessarily indicate that a disease has been cured, since a patient mayrelapse. However, if so, the patient can again be treated with acomposition comprising a CD19×CD3 bispecific antibody as describedherein.

EXAMPLES

The following examples illustrate the invention. These examples shouldnot be construed as to limit the scope of this invention. The examplesare included for purposes of illustration and the present invention islimited only by the claims.

Patients have been treated with blinatumomab and the co-medication ofdexamethasone worked as amelioration, treatment or prophylaxis ofneurological and/or psychiatric adverse events.

The administration of therapeutic dexamethasone was beneficial in thatneurological and/or psychiatric symptoms disappeared without necessityto stop treatment by Blinatumomab.

Patient 109-015 with follicular lymphoma received blinatumomab at a doseof 60 μg/m²/d right from treatment start (i.e. without dose escalationstep) for 4 weeks, the patient additionally received dexamethasone ondays 4-5: 3×8 mg p.o. and on days 6-7: 1×8 mg p.o. in order to treatheadache. This treatment cycle had not to be discontinued due toneurological/psychiatric adverse events.

Patient 109-017 with follicular lymphoma received blinatumomab at a doseof 60 μg/m²/d right from treatment start (i.e. without dose escalationstep) for 5 weeks; in order to treat tremor dexamethasone was givenp.o.: day 7: 8 mg-4 mg-4 mg; day 8+9: 8 mg-4 mg-0 mg; day 10-11: 4 mg-4mg-0 mg; day 12-15: 4 mg-0 mg-0 mg)). This treatment cycle had not to bediscontinued due to neurological/psychiatric adverse events.

Patient 109-026 with MCL received blinatumomab at a dose of 5 μg/m²/dfor 1 week followed by 60 μg/m²/d for the remaining 6 weeks. The patientreceived dexamethasone p.o. in order to treat apraxia on day d11: 3×8 mgand on day 12: 2×8 mg. This treatment cycle had not to be discontinueddue to neurological/psychiatric adverse events.

Patient 135-001 with DLBCL received blinatumomab at 5 μg/m²/d for oneweek, at 15 μg/m²/d for the 2^(nd) week, and 60 μg/m²/d for 4 more days.The patient received dexamethasone in order to treat tremor at 5 μg/m²/don d3 (3×8 mg) continued in decreasing dose over less than a week. Therewere no neurological events after escalation to 15 ug, which could beexplained by a prophylactic effect of dexamethasone. However, on day 4after step to 60 μg/m²/d the patient had to stop due toneurological/psychiatric adverse events which occurred too fast tointervene with dexamethasone.

Patient 109-036 with follicular lymphoma was treated with 5 μg/m²/d forthe first week followed by treatment at 60 μg/m²/d blinatumomab for theremaining 6 weeks of treatment. The patient experienced neurologicaladverse events (tremor and apraxia) starting on day 11, i.e. four daysafter the step to 60 μg/m²/d. Dexamethasone was administered i.v. (3×8mg) and the neurological adverse events resolved under continuedtreatment with blinatumomab.

Patient 109-038 with DLBCL received blinatumomab at 5 μg/m²/d for oneweek, at 15 μg/m²/d for the 2^(nd) week, and 60 μg/m²/d for theremaining 6 weeks of treatment. On day 15, the patient developedintention tremor which resolved after dexamethasone (3×8 mg i.v.) wasgiven (continued blinatumomab treatment).

Patient 109-039 with MCL received blinatumomab at 5 μg/m²/d for oneweek, at 15 μg/m²/d for the 2^(nd) week, and 60 μg/m²/d for theremaining 12 days of treatment. On day 17, the patient developed tremorand slight speech disturbance which resolved after dexamethasone; 3×8 mgof dexamethasone i.v. was given (continued blinatumomab treatment).

Patient 153-002 with MCL received blinatumomab at 5 μg/m²/d for oneweek, at 15 μg/m²/d for the 2^(nd) week, and 60 μg/m²/d for one week.The patient developed slight speech problems on day 4 which completelyresolved after dexamethasone was given (3×8 mg p.o.), in decreasingdoses over a few days. On day 22 the patient had to stop treatment dueto paresis which disappeared without intervention.

Besides the therapeutic use of dexamethasone to mitigate neurologicaladverse events, dexamethasone was also used as prophylaxis in order toprevent neurological adverse events.

Patient 135-002 with DLBCL received blinatumomab at 5 μg/m²/d for oneweek, at 15 μg/m²/d for the 2^(nd) week, and 60 μg/m²/d for theremaining 2 weeks and in addition received dexamethasone prophylaxis(dose: 3×8 mg on day of start of blinatumomab treatment and on days ofdose escalation steps). The patient did not have to discontinuetreatment with blinatumomab due to neurological adverse events.

In patient 155-001 in trial 103-206 with relapsed ALL, was treated witha continuous infusion of blinatumomab at a dosage of 15 μg/m2/d for 16days. The patient was administered dexamethasone before theadministration of blinatumomab in accordance with the teaching of thepresent application Specifically, dexamethasone prophylaxis was given (8mg before treatment start): The patient did not have to discontinuetreatment due to adverse events. The patient achieved a completeremission.

Each of the following 5 patients in trial 103-104 (all with DLBCL) weretreated with blinatumomab continuous infusion at 5 μg/m2/d for the1^(st) week, then 15 μg/m2/d for the 2nd^(t) week, and then 60 μg/m2/dfor the remaining treatment period that could an additional 2-6 weeks.Also each of the following patients were treated prophylactically with20 mg of dexamethasone at twelve hours and 1 hour before the start ofblinatumomab treatment and before each dose increase from the 5 to 15 μgand from 15 to 60 μg.

Patients 135-003 did not have to discontinue due toneurological/psychiatric adverse events.

Patient 108-007 did not have to discontinue due toneurological/psychiatric adverse events. This patient achieved acomplete remission of the lymphoma.

Patient 108-008 did not have to discontinue due toneurological/psychiatric adverse events.

Patient 108-009 did not have to discontinue due toneurological/psychiatric adverse events. This patient achieved anobjective response of the lymphoma.

Patient 108-010 additionally received 100 mg prednisolone one hourbefore start of infusion. The patient did not have to discontinue due toneurological/psychiatric adverse events.

Dexamethasone was used as a prophylaxis for neurological adverse eventsin a 14-y female patient with ALL who was treated with 15 μg/m²/dblinatumomab on a named patient compassionate use base. 4 weeks in firstcycle The patient received dexamethasone on day 1: 3×6 mg p.o., on day2: 2×6 mg p.o. and on day 3: 1×6 mg). The patient did not have todiscontinue treatment due to adverse events. The patient achieved acomplete remission.

A Phase I clinical trial was performed in patients with various B-NHLincluding DLBCL to evaluate the CD19×CD3 bispecific antibody constructin DLBCL patients. Patients were treated for 4-8-weeks by continuousi.v. administration of the antibody with the following step-wise dosingregimen: first week at 5 μg/m²/d, second week at 15 μg/m²/d and for theremaining treatment period at 60 μg/m²/d.

Two cohorts each with 6 DLBCL patients were enrolled. The two cohortssolely differed by the dose and schedule of the glucocorticoidmedication administered at the beginning of the antibody infusion formitigation of adverse events.

Out of the twelve patients, 5 were male and 7 female. The median age was57 years (range from 24 to 78 years). Patients had received a median of4 prior regimens (range from 2-6). All patients had been exposed torituximab. Eight of the 12 patients had undergone ASCT. Internationalprognostic index (IPI) at screening ranged from 1 to 3 with a median of2. In the first cohort 100 mg prednisolone was administered 1 hour priorto start; and in the second cohort patients received dexamethasone (3×8mg) on days 1, 2, and 3. Before treatment start in the second cohort 20mg dexamethasone was administered at 12 hours and 1 hour prior to theadministration of a CD19×CD3 bispecific antibody construct

Although just one DLT (reversible CNS event grade 3) occurred in theprednisolone DLBCL cohort and, thus, the cohort is considered safe, afurther DLBCL cohort applying prophylactic dexamethasone (3×8 mg atstart of infusion or dose increase and reduction to 3×6 mg or 3×4 mg onthe following 2 days, respectively) was opened to optimize management ofCNS events. In light of one of the first two patients having a DLT dueto a reversible CNS adverse event, a modified “early dexamethasone”schedule (20 mg at −12 to −6 hours and −1 hour, at start of infusion ordose increase, and 3×8 mg during the following 2 days) was introduced totest if earlier and more intensive administration of dexamethasone mayameliorate CNS adverse events. No further DLTs were observed after thisadjustment of the dexamethasone schedule. Thus, both the dexamethasonecohort as well as the “early dexamethasone administration” areconsidered safe. Among a total of 5 patients with DLBCL treated with the“early dexamethasone schedule” no DLT was observed. Therefore, it wasconcluded that additional administration of “early dexamethasone” is thesafest way to administer blinatumomab to patients with DLBCL. Also forpatients with “early dexamethasone” objective responses have beenobserved.

1.-13. (canceled)
 14. Kit comprising a GC and a CD3 binding domain andinstructions for use and/or an imprint indicating that the GC is to beemployed for the treatment amelioration and/or prophylaxis ofneurological adverse events caused by said CD3 binding domain
 15. Amethod for amelioration, treatment or prophylaxis of neurologicaladverse events caused by administration of a CD3 binding domaincomprising the step of administering an effective amount of aglucocorticoid (GC).
 16. The method of claim 15 wherein said GC isdexamethasone.
 17. The method of claim 15, wherein GC is administeredprior to, subsequently to and/or in combination with the CD3 bindingdomain.
 18. The method of claim 15, wherein a first dose of the CD3binding domain is administered for a first period of time andconsecutively a second dose of the CD3 binding domain is administeredfor a second period of time, wherein the second dose exceeds the firstdose.
 19. The method of claim 18, wherein after a first and second doseof the CD3 binding domain for a first and second period of time,administering a third dose of the CD3 binding domain, wherein the thirddose exceeds the first and second dose.
 20. The method of claim 19,wherein the GC is administered prior to the administration of the firstdose of the CD3 binding domain and prior to the administration of thesecond dose and/or third dose of the CD3 binding domain.
 21. The methodof claim 15, wherein said neurological adverse event is one or more ofdisturbances of the senses, seizures, encephalopathy, cerebral edema,confusion, ataxia, apraxia, speech disorder, hallucinations, paresis,tremor, headache or disorientation
 22. The method of claim 15, whereinthe GC is administered subsequent to the appearance of the neurologicaladverse event.
 23. The method of claim 15, wherein said CD3 bindingdomain is a bispecific single chain antibody.
 24. The method of claim23, wherein said bispecific single chain antibody is a CD19×CD3bispecific single chain antibody
 25. The method of claim 24, whereinsaid CD19×CD3 bispecific single chain antibody is MT103.
 26. The methodof claim 1, wherein said patient is a human.
 27. The method of claim 1,wherein said patient is characterized by a B/T-cell ratio of less than1:5.